WO2006125483A1 - Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating - Google Patents

Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating Download PDF

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WO2006125483A1
WO2006125483A1 PCT/EP2006/001949 EP2006001949W WO2006125483A1 WO 2006125483 A1 WO2006125483 A1 WO 2006125483A1 EP 2006001949 W EP2006001949 W EP 2006001949W WO 2006125483 A1 WO2006125483 A1 WO 2006125483A1
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polymer
copolymer
characterized
ii
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PCT/EP2006/001949
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German (de)
French (fr)
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Christian Meier
Karin Knuppen
Hans-Ulrich Petereit
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Evonik Röhm Gmbh
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Abstract

The invention relates to the use of mixture of 2 to 60 wt. % of one or more polymers (I) with 40 to 98 wt. % of one or more polymers (II), whereby the polymer (I) is a (meth)acrylate copolymer, containing 90 to 100 wt. % radically polymerised of 40 to 95 wt.% of C1 to C4 alkyl esters of acrylic or methacrylic acid and 5 to 60 wt. % of units of (meth)acrylate monomers with an anionic group with 0 to 10 wt. % of further vinylic polymerisable monomers and polymer(II) is a vinyl polymer different from polymer (I) or a polysaccharide or a derivative of a polysaccharide, containing 88 to 100 % neutral monomer units and up to 12 wt. % polymerisable monomer units with ionic groups, for production of a coated pharmaceutical formulation, containing an active agent core and a polymeric coating made from the mixture of polymers (I) and (II), characterised in that the glass temperature of polymer (I) is not more than 70 °C and an active agent release profile is achieved, whereby the agent release is delayed with relation to a pharmaceutical formulation with a coating made exclusively of polymer (I), starting with the same pH. The invention further relates to a pharmaceutical formulation with a selected polymer (I).

Description

Use of polymer mixtures for preparing coated dosage forms and dosage form with polymeric mixed coating

The invention relates to the use of polymer mixtures for the production of coated dosage forms as well as a pharmaceutical form with polymeric mixed coating.

State of the art

The use of so-called neutral methacrylate copolymers, that is, methacrylate copolymers, which consist of (at least 95%) of predominantly (meth) acrylate monomers with neutral radicals, such as methyl methacrylate or ethyl acrylate, as coating agents and binders for pharmaceutical forms having sustained release has long been known. Uses in mixtures with anionic dispersions are described, for. Example in EP-A 152 038, EP-A 208 213 or EP-A 617 972. WO 01/68767 describes the preparation of dispersions containing neutral methyl acrylate copolymers, using 1 - 10 wt .-% of a nonionic emulsifier having a HLB value of 15, from 2 to 17.3. These measures allowed it while maintaining the stability of the dispersion and its particle size distribution, make it drug formulations in which phase separation with formation of crystal structures is omitted by the emulsifier.

EP 0152038 A2 describes pharmaceutical forms coated with mixed coatings from water-soluble polymers containing carboxyl groups and water-insoluble, film-forming polymers. The polymers may be present in ratios of 60: 40 to 5: present 95th For example, mixed coatings are described of polymers which may be composed of equal parts of ethyl acrylate and methacrylic acid and the other of polymers into one, are composed of ethyl acrylate and methyl methacrylate in a ratio of 2: 1.

EP 0208213 A1 is near identical in content to EP 0152038 A2, however, additionally discloses the effect of high extensibility and elasticity appropriate mixed coatings.

EP 0704208 A2 describes coating agents and binders for pharmaceutical coatings soluble in intestinal juice. These are copolymers of 10 to 25 wt .-% methacrylic acid, 40 to 70 wt .-% of methyl acrylate and 20 to 40% by weight methyl methacrylate. The description mentions multilayer coating systems in addition to monolayer coatings. These can consist of a core z. B. a basic or contains a water-sensitive active ingredient, have a sealing layer of another coating materia !, such as cellulose ethers, or a cationic polymethacrylate, Celluloseester. B. Type of EUDRAGIT®, including EUDRAGIT® RS and RL, and are then additionally provided with the above-mentioned intestinal juice-soluble coating.

WO 03/072087 describes a process for producing a pharmaceutical form in which a copolymer is used which is made of

20-34 wt .-% methacrylic acid and / or acrylic acid, 20 to 69 wt .-% of methyl acrylate and 0 to 40 wt .-% ethyl acrylate and / or optionally 0 to 10 wt .-% further vinylically copolymerizable monomers

composed, with the proviso that the glass transition temperature of the copolymer according to ISO 11357-2, subsection 3.3.3, is not more than 60 0 C. To control the release of active ingredient, it may be advantageous in individual cases to blend the copolymer further polymers. The proportion of other polymers in the mixture can vary within a wide range and is between 1 and 99%, preferably between 10 and 90 wt .-%, particularly preferably between 25 and 85 wt .-% .- based on the polymer blend weight.

Examples of such further polymers include polyvinylpyrrolidones, polyvinyl alcohols, anionic (meth) acrylate copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid (EUDRAGIT ® L 100, EUDRAGIT ® S 100, EUDRAGIT ® L 100-55). Anionic (meth) acrylate copolymers of methyl methacrylate, methyl acrylate and methacrylic acid of the prior art (see for example EP-A 0704207 or EP-A 0 704 208), carboxymethylcellulose salts, hydroxypropylcellulose (HPMC), neutral (meth) acrylate copolymers of methyl methacrylate and ethyl acrylate (dry substance of EUDRAGIT ® NE 30 D), copolymers of methyl methacrylate and butyl methacrylate (Plastoid ® B) or (meth) acrylate copolymers with quaternary ammonium groups (EUDRAGIT ® RL, EUDRAGIT ® RS).

WO 2004/096185 describes a process for producing a coated drug form or a drug form in the form of an active ingredient matrix, by processing a copolymer, an active pharmaceutical ingredient, a core if present and / or pharmaceutically customary excipients in a conventional manner by melting, injection molding, extrusion to a coated drug form and / or processed to form an active ingredient matrix, being used wet granulation, casting, dipping, spreading, spraying or compression, a copolymer derived from up

20-33 wt .-% methacrylic acid and / or acrylic acid, 5 to 30 wt .-% of methyl acrylate and 20 to 40 wt .-% ethyl acrylate and more than 10% to 30 wt .- butyl methacrylate and optionally

O to 10 wt .-% of further vinylically copolymerizable monomers, where the proportions of the monomers add up to 100 wt .-%,

composed, with the proviso that the glass transition temperature of the copolymer is 55 to 70 0 C.

To control the release of active ingredient, it may be advantageous in individual cases to blend the copolymer further polymers. The proportion of other polymers in the mixture can vary within wide ranges and is between 5 and 95, preferably between 10 and 90 wt .-%, particularly preferably between 25 and 85 wt .-%.

Examples of such further polymers include polyvinylpyrrolidones, polyvinyl alcohols, anionic (meth) acrylate copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid (EUDRAGIT ® L 100, EUDRAGIT ® S 100, EUDRAGIT ® L 100-55). acrylate anionic (meth) acrylate copolymers of methyl methacrylate, methyl acrylate and methacrylic acid of the prior art (see for example EP-A 0704207 or EP-A 0704208), carboxymethylcellulose salts, hydroxypropylcellulose (HPMC), neutral (meth) copolymers of methyl methacrylate and ethyl acrylate (dry substance of EUDRAGIT ® NE 30 D), copolymers of methyl methacrylate and butyl methacrylate (Plastoid ® B) or (meth) acrylate copolymers with quaternary amino groups (EUDRAGIT ® RL, EUDRAGIT ® RS). Problem and Solution

EP 0152038 A2 is directed to pharmaceutical forms with coatings of polymers containing carboxyl groups. These carboxyl-containing polymers, in particular methacrylic acid-containing (meth) acrylate copolymers are resistant to gastric juices and soluble in intestinal fluid but at the same time. Depending on the content of carboxyl groups they dissolve at a specific pH values. With a polymer of equal parts of ethyl acrylate and methacrylic acid-coated dosage forms release the active ingredient z. B. from about pH 5.5 to quickly release. According to EP 0152038 A2, the effect is observed when mixing of water-insoluble, film-forming polymers, that the trigger pH shifts to the above, the active ingredient release characteristics and their variation in time but remains substantially unaffected. The effect of the mixture can be described as "pH shift." If we want to influence the timing of the drug release characteristics, so this is obviously only by the amendments of the monomer composition of the carboxyl-containing polymer possible. One skilled in the field of pharmaceutical technology the problem is confronted with that he has only a limited number of polymers. therefore he would have to develop new polymers with new monomer to obtain variants, which can be represented pH values ​​of other time profiles of the active ingredient release characteristics with the same resolution.

It should, therefore, to find a solution that makes it possible to easily change the timing of the active ingredient release characteristics of anionic or carboxyl-containing polymer, without affecting the dissolution pH. The object is achieved by the

Use of a mixture of 2 to 60 wt .-% of one or more polymers (I) with 40 to 98 wt .-% of one or more polymers (II), wherein

the polymer (I) is a (meth) acrylate copolymer containing 90% to 100 wt .- free-radically polymerized units of 40 to 95 wt .-% of Ci to C 4 - alkyl esters of acrylic or methacrylic acid and 5 to 60 wt .-% units of (meth) acrylate monomers having an anionic group, and 0 to 10 wt .-% of other vinylically polymerizable monomers, and

the polymer (II) is the polymer (I) miscellaneous vinyl polymer or a polysaccharide or a derivative of a polysaccharide containing 88 to 100% neutral monomer units and up to 12 wt .-% of polymerized monomer units having ionic groups,

(II) for the preparation of a coated dosage form comprising an active substance-containing core and a polymeric coating from the mixture of polymers (I) and

characterized, in that

the glass transition temperature of the polymer (I) not more than 70 0 C, and a drug release profile is obtained, wherein the active ingredient compared with one with the polymer (I) alone coated pharmaceutical form, starting at the same pH value, however, slowed down is released.

Those described in EP 0152038 A2 (meth) acrylate copolymers, z. As EUDRAGIT® L or EUDRAGIT ® L 100-55, have glass transition temperatures of about 100 0 C. Polymers of this type are not suitable as the polymer (I) for the purposes of the invention. The invention is based on the recognition that the described in EP 0152038 A2 for the described therein polymer blends "pH-Shift" does not stop effect at a variety of anionic or carboxyl-containing polymers whose glass transition temperature is not more than 70 0 C. . In these polymers is quite found without changing the breaking-pH, surprisingly, the task-related effect of the change in the time profile of the active ingredient release characteristics.

Part of the included polymer blends are known in principle from WO 03/072087 and WO 2004/096185. In accordance with the broad teachings of EP 0,152,038 A2 it was assumed that the mixtures described therein, would lead to an present invention not desired pH-shift effect. The use of selected mixtures from WO 03/072087 and WO 2004/096185 to achieve the object, thus opening up new prospects for pharmaceutical technology. The skilled artisan can adjust the time course of the drug release characteristics over the mixing ratio of polymers starting from an intestinal juice-soluble active ingredient release characteristics of anionic or carboxyl-containing polymer with associated specific resolver pH values. This costly alternative developments, special complicated overcoat formulations or the development of polymers can be avoided with alternative monomer composition.

Copolymers of 10 to 30 wt .-%, methyl methacrylate 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% methacrylic acid are known from EP 0704208 A2. Blends with other polymers corresponding to polymer described here the type (II), have been hitherto apparently not discussed. Here, too, would have been according to the broad teaching of EP O 152 038 A2 to be expected that such mixtures would lead to the known pH-shift effect. Again, the invention is based on the recognition that the described in EP 0152038 A2 for the described therein polymer mixtures pH-shift effect is not set at a variety of anionic or carboxyl-containing polymers whose glass transition temperature is not more than 70 0 C. but results in the task-related effect of the change in the time profile of the active ingredient release characteristics without altering the dissolution pH value.

In particular, the object is therefore achieved by a

Dosage form containing, characterized in a drug-containing core which is coated with a polymer mixture coating, that the mixture coating a mixture of 2 to 60 wt .-% of a polymer (I) (with 40 to 95 wt .-%, and one or more polymers II),

characterized, in that

the polymer (I) is a copolymer of 10 to 30 wt .-%, methyl methacrylate 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% methacrylic acid and the polymer (II) from the polymer (I) miscellaneous vinyl polymer is composed from 90 to 100% of neutral vinylically polymerized monomer units and may contain up to 10 wt .-% vinyl-polymerized monomer units having ionic groups.

Embodiment of the invention

Mixing ratios of polymer (I) to polymer (II)

The mixture contains or consists essentially or preferably 100% from 2 to 60, preferably 2 to 30 wt .-% of one or more polymers (I) and 40 to 98, preferably 70 to 98 wt .-% of one or more polymer (II). In this area all the transitions between the release profiles of the polymers (I) and (II) can be set approximately so that the skilled person standing by a new alternative for the formulation of pharmaceutical forms.

A preferred mixture contains or consists essentially or preferably 100% of 2 to 15 wt .-% of one or more polymers (I) with 85 to 98 wt .-% of one or more polymers (II). In this area is surprisingly already by a relatively low proportion of the polymer (I), directed the undesirable strong retarding release characteristics of the polymer (II) in an area which for a long-lasting, approximately constant release of a variety of active ingredients in the various sections of the intestine is desirable from a therapeutic point of view. the active ingredient is preferably at the pH value at which begins to dissolve the polymer (I), in the USP release test (USP 28-NF23) in 60 minutes to less than 50% is released. It is particularly advantageous when the active substance starts at the pH at which the polymer (I) to dissolve, in the USP release test is released in 60 minutes to more than 10%. Here, the degree of liberation is always influenced by the layer thickness of the coating. This can be increased or decreased at a given mixing ratio to control the release in the desired range.

The release may USP, in particular USP 28-NF23, General Chapter <711>, Dissolution, Apparatus 2 (paddle), Method <724> "Delayed Release (Enteric Coated) Articles-General General Drug Release Standard", Method B (100 rpm, 37 0 C) with the following modification: The coated pellets were first placed for 120 minutes in artificial gastric juice (USP) at pH 1, 2 tested for gastric juice resistance, subsequently is rebuffered with phosphate buffer to pH 7.5, representing an artificial intestinal environment corresponds. The active compound concentration in the test medium can be determined photometrically, depending on the active ingredient, for. example.

Polymers (I)

glass transition temperature

The glass transition temperature of the polymer (I) is not more than 70 0 C., preferably 45-68 0 C.

Glass transition temperature is according to ISO 11357-2, item 3.3.3 here in particular the midpoint temperature T mg. The measurement takes place without added plasticizer, with residual monomer contents (REMO) of less than 100 ppm, with a heating rate of 10 ° C / min and under a nitrogen atmosphere. Composition of the polymer (I)

The polymers (I) are (meth) acrylate copolymers, containing or consisting of 90 to 100, preferably 95 to 100, particularly preferably 100 wt .-% of 40 to 95, preferably 66 to 95 wt .-% radically polymerized units of Ci to C 4 -alkyl esters of acrylic or methacrylic acid and 5 to 60, preferably 5 to 34 wt .-% units of (meth) acrylate monomers having an anionic group. Optionally may contain 0 to 10 wt .-% of residues of other vinylically poylmerisierbaren monomers in the polymer (I).

Cr to C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

A (meth) acrylate monomer having an anionic group may, for. However, as acrylic acid, preferably methacrylic acid.

In general, the proportions of Cr mentioned add up to C 4 -alkyl esters of acrylic or methacrylic acid and the (meth) acrylate monomers having an anionic group to 100 wt .-%. Most commercial polymers (I) contain no residues of other types of monomers.

However, there may in addition, without this leading to an impairment or alteration of the essential properties of the polymers (I), small amounts in the range of 0 to 10, z. For example, 1 to 5 wt .-% further vinylically copolymerizable monomers, such. Example, hydroxyethyl methacrylate or hydroxyethyl acrylate, vinyl pyrrolidone, Vinylmalonsäure, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof may be contained. Preferably, however, no further vinylically copolymerizable monomers are included. The glass transition temperature of the polymer (I) is not more than 70, preferably 40 to 70, particularly preferably 45 to 65, in particular 45 to 55 0 C.

Glass transition temperature is according to ISO 11357-2, item 3.3.3 here in particular the midpoint temperature T mg. The measurement takes place without added plasticizer, with residual monomer contents (REMO) of less than 100 ppm, with a heating rate of 10 ° C / min and under a nitrogen atmosphere.

Dispersions / partial neutralization

The polymer (I) is an emulsion polymer typically and preferably is produced in the form of a 10 to 50 parts by weight prozent.igen, especially 20 to 40 percent aqueous dispersion and applied. As a commercial form, a solid content of 30 wt .-% is preferred. For processing a partial neutralization of the methacrylic acid units can be dispensed with; It is however possible, for example, to an extent up to 5 or 10 mol%, when a stabilizing or thickening of the coating agent dispersion is desired. The weight-average latex particle size (radius) is 40 to 100 nm in general, preferably 50 to 70 nm, which ensures favorable processing viscosity below 1000 mPa s. The particle size may be determined by laser diffraction, for example. be determined using the Mastersizer 2000 (Fa. Malvern), B..

At higher degrees of neutralization, eg. B. 10 to 50 mol .-%, or complete neutralization, it is possible to convert the copolymer in a dissolved state. To a solution of the anionic copolymer is generally a full or partial neutralization of the acid groups is necessary. The anionic copolymer may, for. B. be stirred gradually in a final concentration of 1 to 40 wt .-% in water and are thereby neutralized partially or completely by adding a basic substance such. For example, NaOH, KOH, ammonium hydroxide or organic bases such. As triethanolamine. It is also possible to use a powder of the copolymer, the already during its production to the purpose of (partial) neutralization a base such. B. NaOH was added so that the powder is an already (partially) neutralized polymer. The pH of the solution is usually over 4, eg. Eg in the range from 4 to about 7. One possible also for. make mixtures of batches example of fully or partially neutralized dispersions with unneutralized dispersions and processed in the described manner, ie the mixture for coatings use or first freeze to a powder or spray drying.

The dispersion can for. B. spray-dried in a conventional manner or be freeze-dried and provided in the form of a redispersible powder (see, for. Example, EP-A 0262 326). Alternative methods are freeze-drying or coagulation and squeezing of water in an extruder, followed by granulation (see, for. Example, EP-A 0 683 028).

Surprisingly, it was found that the copolymer dispersions of spray- or freeze-dried and redispersed powders having increased shear stability. This is particularly the spray advantage. This advantage is particularly apparent enhanced when the copolymer contained in the dispersion to 2 to 10, preferably 5 to 7 mol% in neutralized form is present (based on the copolymer contained in the acid groups). For this purpose, preferably, the neutralization by adding NaOH. Preferably, an anionic emulsifier is included in amount of 0.1 wt .-% to the second Particularly preferably sodium lauryl sulfate is as an emulsifier.

Polymer (I) type containing 5% to 15 wt .- methacrylic acid

Suitable polymers (I), known from EP 0704208 A2, 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% are (meth) acrylate copolymers consisting of 10 to 30 wt .-%, methyl methacrylate, methacrylic acid (type EUDRAGIT® FS). The pH of the start of the specific active ingredient release in intestinal juice or simulated intestinal fluid can be stated to be pH 7.0. The glass transition temperature of this polymer (I) is preferably 45 to 55 0 C.

EUDRAGIT® FS is a copolymer of 25 wt .-% methyl methacrylate, 65 wt .-% of methyl acrylate and 10 wt .-% methacrylic acid. Eudragit® FS 30 D is a dispersion comprising 30 wt .-% Eudragit® FS. The glass transition temperature T m g according to ISO 11357-2, subsection 3.3.3 is about 48 0 C.

Polymer (I) type having 20 to 34 wt .-% methacrylic acid and good Reißdehnungseigenschften

Further suitable polymers (I) are copolymers known from WO 03/072087, from

20-34 wt .-% methacrylic acid and / or acrylic acid, 20 to 69 wt .-% of methyl acrylate and 0 to 40 wt .-% ethyl acrylate and / or optionally 0 to 10 wt .-% further vinylically copolymerizable monomers

with the proviso that the proportions of monomers are selected so that the glass transition temperature of the copolymer according to ISO 11357-2, subsection 3.3.3, is not more than 60 0 C. This (meth) acrylate copolymer is suitable to tablets because of its good elongation at break, for compressing pellets.

The abovementioned copolymer is composed in particular of free-radically polymerized units of

20 to 34, preferably 25 to 33, particularly preferably 28 to 32 wt .-% of methacrylic acid or acrylic acid, preferably methacrylic acid,

20 till 69, preferably 35 to 65, particularly preferably 35 to 55 wt .-% of methyl acrylate and, optionally,

0 to 40, preferably 5 to 35, particularly preferably 15 to 35 wt .-% ethyl acrylate, with the proviso that the glass transition temperature of the copolymer (measurement without added plasticizer (at a residual monomer content REMO) of less than 100 ppm, heating rate 10 ° C / min, nitrogen atmosphere) according to ISO 11357-2, subsection 3.3.3 (T mg), at most 60, preferably 40 to 60, particularly preferably 45 to 55 0 C.

The copolymer preferably consists essentially to exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the above proportions indicated. However, there may in addition, without this leading to an impairment of the essential properties, for small amounts in the range of 0 to 10, z. For example, 1 to 5 wt .-% further vinylically copolymerizable monomers, such. As methyl methacrylate, butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate may be contained.

To adjust specific release profiles or release sites also mixtures of said copolymers can be used.

Glass transition temperature is according to ISO 11357-2, item 3.3.3 here in particular the midpoint temperature T mg. The measurement takes place without added plasticizer, with residual monomer contents (REMO) of less than 100 ppm, with a heating rate of 10 ° C / min and under a nitrogen atmosphere.

The copolymers are obtained in manner known per se by free-radical bulk, solution, bead or emulsion polymerization. They must be brought in the inventive particle size range before processing by suitable grinding, drying or spraying. This can be done by simple breaking of extruded and cooled pellets or hot cut.

Especially on mixture with other powders or liquids, the use of powders may be advantageous. Suitable apparatuses for producing powders are familiar to the skilled artisan, for. As air jet mills, pin mills, compartment mills. If necessary, appropriate sieving steps can be included. A suitable mill for industrial large quantities is for example an opposed jet mill (Multi no. 4200), which is operated at about 6 bar overpressure.

Polymer (I) type having 20 to 33 wt .-% methacrylic acid with good mechanical properties, for compressing pellets to tablets.

Further suitable polymers (I) are copolymers, known from WO 2004/096185, from

20-33 wt .-% methacrylic acid and / or acrylic acid, 5 to 30 wt .-% of methyl acrylate and 20 to 40 wt .-% ethyl acrylate and more than 10% to 30 wt .- butyl methacrylate and optionally

0 to 10 wt .-% of further vinylically copolymerizable monomers, where the proportions of the monomers add up to 100 wt .-%,

with the proviso that the proportions of monomers are selected so that the glass transition temperature of the copolymer (glass transition temperature) according to ISO 11357-2, subsection 3.3.3 (midpoint temperature T m), is 55 to 70 0 C. Copolymers of this type are suitable for tablets because of their good mechanical properties, for compressing pellets.

The abovementioned copolymer is composed in particular of free-radically polymerized units of 20 to 33, preferably 25 to 32, particularly preferably 28 to 31 wt .-% of methacrylic acid or acrylic acid, preferably methacrylic acid,

5 to 30, preferably 10 to 28, particularly preferably 15 to 25 wt .-% methyl acrylate,

From 20 to 40, preferably 25 to 35, particularly preferably 18 to 22 wt .-% ethyl acrylate, and

greater than 10 to 30, preferably 15 to 25, particularly preferably 18 to 22 wt .-% of butyl methacrylate

together, wherein the monomer composition is chosen so that the glass transition temperature of the copolymer 55 to 70 0 C, preferably 59 to 66, particularly preferably 60 to 65 0 C.

The copolymer preferably consists essentially to exclusively of 90, 95 or 99 to 100 wt .-%, of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the quantitative ranges indicated above.

However, there may in addition, without this necessarily leading to an impairment of the essential properties, for small amounts in the range of 0 to 10, z. For example, 1 to 5 wt .-% further vinylically copolymerizable monomers, such. As methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, Vinylmalonsäure, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof may be contained. Polymers (II)

The polymer (II) is the polymer (I) miscellaneous vinyl polymer or a polysaccharide or a derivative of a polysaccharide which is composed of 80 to 100% of neutral monomer units and up to 12 wt .-% monomer units may contain with ionic residues.

vinyl polymers

The polymer (II) may be a vinyl polymer containing 88 to 100% neutral vinylically polymerized monomer units and up to 12 wt .-% vinyl-polymerized monomer units having ionic groups.

The polymer (N) may be a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethylammoniumethyl methacrylate, a polyvinyl-pyrrolidones (PVP), polyvinyl alcohols, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR), polyvinyl acetate (PVAc, Kollicoat ® SR), vinyl acetate-vinylpyrrolidone copolymer (Kollidon® VA64), vinyl acetate: crotonic acid copolymer 9: 1 (VAC: CRA, Kollicoat® VAC),

Polysaccharides or derivatives

The polymer (II) may be a polysaccharide or the derivative of a polysaccharide containing 88 to 100% neutral monomer units and up to 12 wt .-% of polymerized monomer units having ionic groups, to be. The polymer (II) may be: starch and derivatives thereof, hydroxyethyl cellulose (HEC, Klucel, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat, Methocel, Sepifilm®, Viscontran®, Opadry®,), Hydroxymehylethylcellulose (HEMC) , ethylcellulose (EC, Ethocel ®, Aquacoat ®, Surelease ®) of the aforementioned polymers, methyl cellulose (MC, Viscontran®, Tylopur®, Methocel®), Celluloseester, cellulose glycolate or a mixture thereof.

(Meth) acrylate copolymers

Neutral (meth) acrylate copolymers

The polymer (II) may, in particular from a polymer (I) Various (meth) acrylate copolymer containing 88 to 100% neutral monomer units and up to 12 wt .-% of polymerized monomer units having ionic groups.

10 wt .-% of a nonionic emulsifier having an HLB value of 15, 2 to 17.3 were prepared -. Neutral methyl, which, according to WO 01/68767 as dispersions using 1 are preferred The latter offer the advantage that phase separation with formation of crystal structures is omitted by the emulsifier.

The polymer (II) may be a copolymer of 20 to 40% by weight ethyl acrylate and 60 to 80 wt .-% methyl methacrylate (type EUDRAGIT® NE) is particularly preferred.

Particularly suitable as the polymer (II) is a copolymer of 30 wt .-% ethyl acrylate and 70 wt .-% methyl methacrylate (EUDRAGIT® NE). (Meth) acrylate copolymers with quaternary amino groups

The polymer (II) may further contain from 88 and 98 wt .-% radically polymerized Cr to C 4 -alkyl esters of acrylic or methacrylic acid and 12 to 2 wt .-% (meth) acrylate monomers with a quaternary amino group in the alkyl radical put together.

Preferred Cr to C 4 -alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.

As the (meth) acrylate monomer with quaternary amino groups is 2-trimethylammoniumethyl chloride is particularly preferred.

The polymer (II), a copolymer of 50-70 wt .-% methyl methacrylate, 20 - 40 wt .-% ethyl acrylate and 12 to 2 weight trimethylammoniumethyl methacrylate chloride (type EUDRAGIT® RS / RL).

be a specifically suitable copolymer comprises 65 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 5 wt .-% 2-Trimethylammoniumethylmethacrylat- constructed chloride (EUDRAGIT® RS).

A specifically suitable copolymer comprises 60 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 10 wt .- be constructed% 2-Trimethylammoniumethylmethacrylat- chloride (EUDRAGIT® RL).

Active ingredient-containing pellets can be produced by applying means of a layering agent. For this purpose, active ingredient is dissolved together with further excipients (release agent, optionally a plasticizer) and homogenized in a binder or suspended. By means of a fluidized bed process, the liquid can be applied to placebo pellets or other suitable carrier materials, the solvent or suspending agent being evaporated (Literature: International Journal of Pharmaceutics 143, P. 13 - 23). After manufacturing a drying step may follow. The active ingredient can be applied in several layers.

Some drugs, such. As aspirin, are commercially available in the form of active ingredient crystals and can be used in this form, instead of active substance-containing pellets.

Film coatings on active substance-containing pellets are normally applied in fluidized bed apparatuses. Formulation examples are mentioned in this application. Film formers are normally mixed with plasticizers and release agents by a suitable process. Here, the film former can be present as a solution or suspension. The excipients for film formation may likewise be dissolved or suspended. Organic or aqueous solvents or dispersants can be used. To stabilize the dispersion stabilizers may also be used (for example Tween 80, or other suitable emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and other substances mentioned in the literature. Between the active ingredient layer and copolymer layer according to the invention a separating layer can be applied, which serves to separate active ingredient and coating material for the purpose of preventing interactions. This layer may consist of inert film formers (such as HPMC, HPC or (meth) acrylic acid copolymers) or, for example, talc or other suitable pharmaceutical substances. Likewise, combinations of film forming agents and talc or similar substances can be used.

It is also possible a separating layer of partially or completely neutralized copolymer dispersions.

Mixes for the preparation of tablets from coated particles are prepared by mixing the pellets with suitable binders for tableting, if necessary adding disintegration-promoting substances and, if necessary, the addition of lubricants. Mixing can take place in suitable machines. Unsuitable mixers, which cause damage to the coated particles, for example. B. ploughshare mixers. To achieve suitable short disintegration times a specific sequence of addition of excipients to the coated particles may be required. By premixing of the coated particles with the lubricant or mold release agent magnesium stearate whose surface to be rendered hydrophobic, and so to prevent sticking.

For tabletting, suitable mixtures usually 3 to 15 wt% of a disintegrant include, for. As Kollidon CL and z. For example, 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate. The binder content is determined by the required proportion of coated particles. Typical binders are, for. B. Cellactose ®, microcrystalline cellulose, calcium phosphates, Ludipress ®, lactose or other suitable sugars, calcium sulfates or starch derivatives. Substances are preferably of low bulk density.

Typical disintegrating agents (disintegrants) are crosslinked starch or cellulose derivatives, and quervemetztes polyvinylpyrrolidone. Cellulose derivatives are also suitable. By selecting a suitable binder, the use of disintegrating agents may be omitted.

Typical lubricants and mold release agents are magnesium stearate or other suitable salts of fatty acids or substances (eg, lauric acid, calcium stearate, talc, etc.) mentioned in the literature for this purpose. The use of appropriate machines (eg tablet press with external lubrication) or suitable formulations can be dispensed with the use of a lubricant and mold release agent in the mixture.

The mixture may optionally contain a flow-improving aid attached (e. Example highly disperse silica derivatives, talc, etc.).

Tableting may be carried out on conventional tablet presses, eccentric or rotary tablet presses, with compressive forces in the range of 5 to 40 kN, preferably 10 - 20 kN. The tablet presses can be equipped with systems for external lubrication. Special systems for die insert, which avoid die by means of stirring blades. polymer mixture

First, a mixture of one or more polymer (I) and one or more polymer (II) is prepared. These z. B. two organic solutions or aqueous dispersions of two proportionately mixed. the mixture of aqueous dispersions of one or more of the polymer (I) and one or more of the polymer (II) is preferably prepared. In general, each is a polymer (I) and employ a polymer (II). The mixture contains 2 to 60, preferably 10 to 55 wt .-% of a polymer (I) with 40 to 98, preferably 45 to 90 wt .-% of one or more polymers (II), where the proportions by weight of 100 % complete. Usually but not necessarily pharmaceutically usual excipients are added in addition, which are optionally dissolved or dispersed separately.

drug form

The invention further relates to a dosage form comprising a selected polymer (I), which is not clear from EP 0152038 A2. The polymer contained in the drug form (II) is identical with the herein described use according eingestezten polymer (II).

Accordingly, the invention relates to a dosage form comprising an active ingredient-containing core which is coated with a polymer mixture coating, characterized in that the mixed coating a mixture of 2 to 60 wt .-% of a polymer (I) with 40 to 95 wt .-%, and is one or more polymers (II),

characterized, in that

the polymer (I) is a copolymer of 10 to 30 wt .-%, methyl methacrylate 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% of methacrylic acid and

the polymer (II) is the polymer (I) miscellaneous vinyl polymer or a polysaccharide or a derivative of a polysaccharide which is composed about 88 to 100% of neutral monomer units and up to 12 wt .-% monomer units may contain with ionic residues.

Polymer (I) type containing 5% to 15 wt .- methacrylic acid

Suitable polymers (I) for the inventive dosage form are known from EP 0704208 A2. Polymers (I) are (meth) acrylate copolymers consisting of 10 to 30 GΘW .-%, methyl methacrylate 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt. ~% Of methacrylic acid (EUDRAGIT® type FS). The pH of the start of the specific active ingredient release in intestinal juice or simulated intestinal fluid can be stated to be pH 7.0. The glass transition temperature of this polymer (I) is preferably 45 to 55 0 C.

EUDRAGIT® FS is a copolymer of 25 wt .-% methyl methacrylate, 65 wt .-% of methyl acrylate and 10 wt .-% methacrylic acid. Eudragit® FS 30 D is a dispersion comprising 30 wt .-% Eudragit® FS. The glass transition temperature 7 mg according to ISO 11357-2, item 3.3.3 is approximately 48 0 C.

General Preparation Procedure for the described pharmaceutical forms

cores

Carriers for the coatings are capsules, tablets, granules, pellets, crystals of regular or irregular shape. The size of granules, pellets or crystals is between 0.01 and 2.5 mm, that of tablets from 2.5 to 30.0 mm. Capsules consist of gelatine, starch or cellulose derivatives.

They usually contain the biologically active substance (active ingredient) up to 95% as well as further pharmaceutical auxiliary substances up to 99.9 wt .-% Customary preparation processes are direct compression, compression of dry, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (eg on plates) or by binding of powders (powder layering) onto active ingredient-free beads (nonpareils) or active ingredient-containing particles.

Besides the active ingredient, they can contain further pharmaceutical excipients: binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegration promoters, lubricants, disintegrants, (meth) acrylates, starch and its derivatives, sugar solubilizers or others.

Producing a pharmaceutical form

Active ingredient-containing pellets z can. Be prepared for example by applying active ingredient means of a layering. For this purpose, active ingredient is dissolved together with further excipients (release agent, optionally a plasticizer) and homogenized in a binder or suspended. By means of a fluidized bed process, the liquid can be applied to placebo pellets or other suitable carrier materials, the solvent or suspending agent being evaporated (Literature: International Journal of Pharmaceutics 143, P. 13 - 23). After manufacturing a drying step may follow. The active ingredient can be applied in several layers.

Some drugs, such. As aspirin, are commercially available in the form of active ingredient crystals and can be used in this form, instead of active substance-containing pellets.

First, a mixture of the polymer (I) and the polymer (II) is prepared. These z. B. Two dispersions proportionately mixed. Film coatings on active substance-containing pellets are normally applied in fluidized bed apparatuses. Formulation examples are mentioned in this application. Film formers are normally mixed with plasticizers and release agents by a suitable process. Here, the film former can be present as a solution or suspension. The excipients for film formation may likewise be dissolved or suspended. Organic or aqueous solvents or dispersants can be used. To stabilize the dispersion stabilizers may also be used (for example Tween 80, or other suitable emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and other substances mentioned in the literature.

Between the drug-containing layer and the coating layer according to the invention a separating layer can optionally be applied, which serves to separate active ingredient and coating material for the purpose of preventing interactions. This layer may consist of inert film formers (such as HPMC, HPC or (meth) acrylic acid copolymers) or, for example, talc or other suitable pharmaceutical substances. Likewise, combinations of film forming agents and talc or similar substances can be used.

It is also possible a separating layer of partially or completely neutralized copolymer dispersions. polymer coating

The polymer coating may preferably be such. B. 2 to 20 wt .-% with respect to the weight of the active ingredient-containing core account. Here, the degree of liberation is always influenced by the layer thickness of the coating. This can be increased or decreased at a given mixing ratio to control the release in the desired range.

topcoat

It is also possible an outer cover layer (topcoat) of a further, preferably water-soluble, polymers, and excipients, such. B. pigments and / or release agents to deposit, which ensures additional functions, such as coloring or prevention of adhesion.

Producing multiparticulate pharmaceutical forms

The coated dosage form is preferably in the form of pellets contained in a multiparticulate pharmaceutical form, in particular in pellet-containing tablets, minitablets, capsules, sachets or reconstitutable powders.

The invention is particularly suitable for producing multiparticulate pharmaceutical forms, since the mixture of the invention can withstand the high pressures in the compression of the pellets with the filler. The coated dosage form is preferably in the form of pellets contained in a multiparticulate pharmaceutical form, in particular in pellet-containing tablets, minitablets, capsules, sachets or reconstitutable powders. The preparation of multiparticulate dosage forms by compressing a pharmaceutically customary binder with active containing particles is z. B. Beckert et al. (1996), "Compression of enteric-coated pellets to disintegrating tablets ,,, International Journal of Pharmaceutics 143, pp 13-23, and in WO 96/01624 in detail.

Active ingredient-containing pellets can be produced by applying means of a layering agent. For this purpose, active ingredient together with - homogenized and dissolved in a binder or suspended further excipients (release agent, optionally a plasticizer). By means of a fluidized bed process, the liquid can be applied to placebo pellets or other suitable carrier materials, the solvent or suspending agent being evaporated (Literature: International Journal of Pharmaceutics 143, P. 13 - 23). After manufacturing a drying step may follow. The active ingredient can be applied in several layers.

Some drugs, such. As aspirin, are commercially available in the form of active ingredient crystals and can be used in this form, instead of active substance-containing pellets.

Film coatings on active substance-containing pellets are normally applied in fluidized bed apparatuses. Formulation examples are mentioned in this application. Film formers are normally mixed with plasticizers and release agents by a suitable process. Here, the film former can be present as a solution or suspension. The excipients for film formation may likewise be dissolved or suspended. Organic or aqueous solvents or dispersants can be used. To stabilize the dispersion stabilizers may also be used (for example Tween 80, or other suitable emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and other substances mentioned in the literature.

Mixes for the preparation of tablets from coated particles are prepared by mixing the pellets with suitable binders for tableting, if necessary adding disintegration-promoting substances and, if necessary, the addition of lubricants. Mixing can take place in suitable machines. Unsuitable mixers, which cause damage to the coated particles, for example. B. ploughshare mixers. To achieve suitable short disintegration times a specific sequence of addition of excipients to the coated Partikenl may be required. By premixing of the coated particles with the lubricant or mold release agent magnesium stearate whose surface to be rendered hydrophobic, and so to prevent sticking.

For tabletting, suitable mixtures usually 3 to 15 wt% of a disintegrant include, for. As Kollidon CL and z. For example, 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate. The binder content is determined by the required proportion of coated particles.

Typical binders are, for. B. Cellactose ®, microcrystalline cellulose, calcium phosphates, Ludipress ®, lactose or other suitable sugars, calcium sulfates or starch derivatives. Substances are preferably of low bulk density. Typical disintegrating agents (disintegrants) are crosslinked starch or cellulose derivatives, and crosslinked polyvinylpyrrolidone. Cellulose derivatives are also suitable. By selecting a suitable binder, the use of disintegrating agents may be omitted.

Typical lubricants are magnesium stearates and Fomnentrennmittel or other suitable salts of fatty acids or substances (eg, lauric acid, calcium stearate, talc, etc.) mentioned in the literature for this purpose. The use of appropriate machines (eg tablet press with external lubrication) or suitable formulations, the use of a lubricant and mold release agent in the mixture is omitted.

The mixture may optionally contain a flow-improving aid attached (e. Example highly disperse silica derivatives, talc, etc.).

Tableting may be carried out on conventional tablet presses, eccentric or rotary tablet presses, with compressive forces in the range of 5 to 40 kN, preferably 10 - 20 kN. The tablet presses can be equipped with systems for external lubrication. Special systems for die insert, which avoid die by means of stirring blades.

release

There is obtained according to the invention an active ingredient release profile, wherein the active ingredient compared with one with the polymer (I) alone coated pharmaceutical form, starting at the same pH value, however, slowed down is released.

There is obtained according to the invention an active ingredient release profile, wherein the active ingredient compared with one with the polymer (II) alone coated pharmaceutical form, but starting at the same pH released faster.

Drug forms in which the active substance at a pH value at which the polymer (I) begins to dissolve, in the USP release test (USP 28 NF23) in 60 minutes to less than 50%, preferably less than 25% being preferred , particularly preferably released to 10 to 50%.

The release test, for example. B. according to USP (according to USP 28-NF23, method B, modified test for "enteric coated products") to the person skilled in the art The test conditions are, in particular:. Paddle method, 100 rpm, 37 0 C, pH 1, 2 with 0.1 N HCl, pH 7.5 by addition of 0.2 M phosphate buffer and adjustment with 2 N NaOH. See also USP 27-NF22 Supplement 1, method "Delayed release" monograph <724> Drug release.

Pharmaceutically customary excipients

The formulation of the invention are preferably added Pharmaceutically customary auxiliaries in the production of the granules or powder. The additives can be also added in the processing of the coating and binding agent. Basically, of course, all substances employed toxicological harmless and particularly in pharmaceuticals without risk for patients must be used. The amounts employed and use of the customary additives in pharmaceutical coatings or layerings are familiar to the skilled artisan. Customary additives such can. As release agents, pigments, stabilizers, antioxidants, pore formers, penetration promoters, gloss agents, aromatizing substances or flavorings be. They serve as processing aids and should guarantee a reliable and reproducible production process and good long-term storage stability or they achieve in the pharmaceutical form additional advantageous properties. They are added to the polymer preparations before processing and can influence the permeability of the coatings, which can optionally be used as additional control parameter.

Caking agent:

Release agents usually have lipophilic properties in general and are usually added to the spray suspensions. They prevent agglomeration of the cores during the film coating. Stearate, ground silica, kaolin or nonionic emulsifiers with an HLB - - Preferably, talc, Mg or Ca value used 3 to 8 Customary use amounts for release agents in the inventive coating and binding agents are from 0.5 to 100 wt .-% based on the dry weight of the dispersion. pigments:

Pigments incompatible with the coating agent are in particular those pigments which, if added directly to the (meth) acrylate copolymer dispersion, for example. Eg by stirring in, in the usual amounts of z. B. 20 to 400 wt .-% based on the dry weight of the (meth) acrylate copolymers to the destabilization of the dispersion, coagulation, lead to inhomogeneity or similarly unwanted effects. Furthermore, the pigments to be used are of course non-toxic and suitable for pharmaceutical purposes. See, for. As well: German Research Foundation, dyes for foods, Harald Boldt Verlag KG, Boppard (1978); . German food Rundschau 74, No. 4, p 156 (1978); Drug dye Regulation AmFarbV from 08.25.1980.

With the coating agent Pigments incompatible can. be as alumina pigments. Incompatible pigments are for. B., sunset yellow, cochineal red lake, colored pigments based on alumina or azo dyes, Sulfonsäurefarbstoffe, orange yellow S (E110, Cl. 15985, FD & C Yellow 6), indigo carmine (E132, Cl. 73015, FD & C Blue 2), tartrazine (E 102, Cl . 19140, FD & C Yellow 5), Ponceau 4R (e 125, Cl. 16255, FD & C Cochineal Red A), Chinolingleb (e 104, Cl. 47005, FD & C Yellow 10), erythrosine (E127, Cl. 45430, FD & C Red 3) , azorubine (e 122, Cl. 14720, FD & C Carmoisine), amaranth (e 123, C. 1. 16185, FD & C Red 2), acid brilliant green (e 142, Cl. 44090, FD & C Green S).

The E numbers indicated for the pigments relate to an EU numbering. See also "German Research Foundation, dyes for foods, Harald Boldt Verlag KG, Boppard (1978); . German food Rundschau 74, No. 4, p 156 (1978); Drug dye Regulation AmFarbV from 08.25.1980. The FD & C numbers relate to the approval in Food, Drugs and Cosmetics by US Food and Drug Administration (FDA) described in: US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations - Title 21 Color additive Regulations Part 82, listing of Certified provisionally Listed Colors and Specifications (21 CFR Part 82).

softener

Other additives can also be plasticizers. The usual amounts are between 0 and 50, preferably 5 to 20 wt .-%.

Plasticizers may influence the functionality of the polymer layer depending on type (lipophilic or hydrophilic) and added amount. Plasticizers achieve through physical interaction with the polymers a reduction in the glass transition temperature and promote a function of the added amount of the filming. Suitable substances usually have a molecular weight from 100 to 20,000 and usually contain one or more hydrophilic groups in the molecule, eg. B. hydroxyl, ester or amino groups.

Examples of suitable plasticizers are alkyl citrates, Glycerinester, phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12,000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS). Mention may furthermore are usually liquid at room temperature esters such as citrates, phthalates, sebacates or castor oil. Citric acid and sebacic acid are preferably used.

Addition of the plasticizers to the formulation can be carried out directly, in aqueous solution or after thermal pretreatment of the mixture in a known manner. Mixtures of plasticizers can be used.

drugs

Common pharmaceuticals in reference to extract, such as the Red List or the Merck Index.

Biologically active substances:

The drugs used in the context of the invention are intended to be used on or in the human or animal body in order

1. to cure diseases, ailments, physical damage or pathological symptoms, alleviate, prevent or diagnose.

2. to reveal the condition, the state or the functions of the body or mental states.

3. to replace the human or animal body generated active substances or body fluids.

4. fend off pathogens, parasites or exogenous substances, eliminate or render harmless or

5. to influence the nature, condition or functions of the body or mental states. The formulation of the invention is suitable for administration in principle any active pharmaceutical ingredients or biologically active substances.

therapy classes

These pharmaceutically active substances, one or more active ingredient classes belong, such as ACE inhibitors, adrenergics, Adrenocortikosteroide, anti-acne agents, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha 1 antagonists, remedies for alcohol abuse, amino acids, amebacidal, anabolics , analeptics, anesthetic additions, anesthetics (non-inhalational), anesthetics (local), analgesics, androgens, angina therapeutic agents, antagonists, antiallergics, antiallergics such as PDE inhibitors, antiallergics for asthma treatment, further antiallergics (for example leukotriene antagonists antianaemic, antiandrogens Antianxiolytika, antiarthritic agents, antiarrhythmic agents, Antiatheriosklerotika, antibiotics, anticholinergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, diuretics, antidotes, antiemetics, antiepileptics, antifibrinolytic agents, antiepileptic agents, anthelmintics, anti-histamines, antihypotensives, antihypertensives, anti-hypertensives, antihypotensives, Antikoa gulantien, antifungals, Antiöströgene, Antiöströgene (non-steroids), anti-parkinsonian agents, anti-inflammatory agents, antiproliferative active ingredients, antiprotozoal active ingredients, antirheumatics, Antischistosomizide, AntiSpasmolytika, antithrombotics, antitussives, appetite suppressants, arteriosclerosis, bacteriostats, beta-blockers, beta-receptor blockers, bronchodilators, carbonic anhydrase inhibitors , chemotherapeutic agents, choleretics, cholinergics, cholinergic agonists, cholinesterase inhibitors, agents for treating ulcerative colitis, Cyclooxigenasehemmer, diuretics, ectoparasiticides, emetics, enzymes, enzyme inhibitors, enzyme inhibitors, agents against vomiting, fibrinolytics, fungistatics, gabapentin, gout remedies, glaucoma therapeutic agents , glucocorticoids, Glucocortikosteroide, haemostatics, cardiac glycosides, histamine H2 antagonists, hormones and their inhibitors, immunotherapeutic agents, cardiotonics, Kokkid iostatika, laxatives, lipid-lowering agents, gastrointestinal therapeutic agents, malaria therapeutic agents, migraine remedies, Mikrobi ozide, Crohn's disease, metastasis inhibitors, migraine remedies, mineral preparations, motilitätssteigemde agents, muscle relaxants, neuroleptics, active ingredients for treatment of estrogens, osteoporosis, otologicals, antiparkinson agents, phytopharmaceuticals, pitavastatin, proton pump inhibitors, prostaglandins, active ingredients for treating benign prostate hyperplasia, agents for the treatment of pruritus, psoriasis drugs, psychotropic drugs, radical scavengers, renin antagonists, thyroid drugs, drugs for the treatment of seborrhea, drugs against seasickness, antispasmodics, alpha- and beta-sympathomimetics, tenatoprazole, platelet aggregation inhibitors, tyrosine kinase inhibitors, tranquilizers, Ulkustherapeutika, more Ulkustherapeutika, means for treating urolithiasis, antiviral agents, antivirals, vitamins, cytokines, agents for combination therapy with cytotoxic drugs, cytostatics.

drugs

Examples of suitable active ingredients are acarbose, acetylsalicylic acid, abacavir, aceclofenac, aclarubicin, acyclovir, actinomycin, adalimumab, adefovir, adefovir dipivoxil, adenosylmethionine, adrenaline and adrenaline derivatives, agalsidase alpha, agalsidase beta, alemtuzumab, almotriptan, Alphacept, allopurinol, almotriptan, alosetron, alprostadil, amantadine, ambroxol, amisulpride, amlodipine, amoxicillin, 5-aminosalicylic acid, amitriptyline, amlodipine, amoxicillin, amprenavir, anagrelide, anakinra, anastrozole, androgen and androgen derivatives, apomorphine, aripiprazole, arsenic trioxide, artemether, atenolol, atorvastatin, atosiban, azathioprine, azelaic acid, barbituric acid derivatives, balsalazide, basiliximab, Beclapermin, beclomethasone, bemiparin, benzodiazepines, betahistine, bexarotene. Bezafibrate, bicalutamide, bimatoprost, bosentan, botulinum toxin !, brimonidine, brinzolamide, budesonide, budipine, bufexamac, bumetanide, buprenorphine, bupropion, Butizin, calcitonin, calcium antagonists, calcium salts, candesartan, capecitabine, captopril, carbamazepine, Carifenacin, carvedilol, caspofungin, cefaclor , cefadroxil, cefalexin cephalosporins, cefditoren, cefprozil, cefuroxime, celecoxib, Cepecitabin, Cerivastatim, cetirizine, cetrorelix, cetuximab, chenodeoxycholic acid, chorionic gonadotropin, ciclosporin, cidofovir, cimetidine, ciprofloxacin, cisplatin, cladribine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, clopidogrel, codeine, caffeine, cholestyramine, cromolyn sodium, cotrimoxazole, coumarin and coumarin derivatives, darbepoetin, cysteamine, cysteine, cytarabine, cyclophosphamide, cyproterone, cytarabine, daclizumab, dalfopristin, danaparoid, dapiprazole, darbepoetin, Defepripron, desipramine, desirudin, Desloaratadin, desmopressin, desogestrel, desonide, dexibuprofen, Dexketopro fen, disoproxil, diazepam and Diazepamderivate, didanosine, dihydralazine, diltiazem, dimenhydrinate, dimethyl sulphoxide, dimeticon, dipivoxil, Dipyridamoi, dolasetron, domperidone and Domperidanderivate, Donepzil, dopamine, doxazosin, doxorubicin, doxylamine, diclofenac, divalproex, dronabinol, drospirenone, drotrecogin alpha , dutasteride, ebastine, econazole, efavirenz, Eletripan, Emidastin, emtricitabine, enalapril, Encepur, entacapone, Enfurvirtid, ephedrine, epinephrine, eplerenone, epoetin and Epoetinderivate, eprosartan, eptifibatide, ertapenem, esomeprazole, estrogen and estrogen derivatives, etanercept, ethenzamide, Ethinöstradiol , etofenamate, etofibrate, etofylline, etonogestrel, etoposide, exemestane, ezetimibe, famciclovir, famotidine, Faropenandaloxat, felodipine, fenofibrate, fentanyl, fenticonazole, fexofenadine, finasteride, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flupirtine, flutamide, fluvastatin , follitropin, fomivirsen, fondaparinux, formoterol, Fosfomicin, Frovatrip tan, furosemide, fusidic acid, Gadobenate, galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin, gefitinib, gemfibrozil, gemopatrilat, gentamicin, gepirone, progestogen and progestogen derivatives, ginkgo, glatiramer, glibenclamide, glipizide, glucagon, glucitol and Glucitolclerivate, glucosamine and glucosamine derivatives, Glykosidantibiotika, glutathione, glycerol and glycerol derivatives, hypothalamus hormones, goserelin, grepafloxacin, gyrase inhibitors, guanethidine, gyrase inhibitors, haemin, halofantrine, haloperidol, urea derivatives as oral antidiabetics, heparin and heparin derivatives, cardiac glycosides, hyaluronic acid, hydralazine, hydrochlorothiazide and Hydrochlorothiazidderivate, hydroxyomeprazole, hydroxyzine, ibritumomab, ibuprofen, idarubicin, Ifliximab, ifosfamide, iloprost, imatinib, glargine imidapril, imiglucerase, imipramine, imiquimod, imidapril, indomethacin, indoramin, infliximab, insulin, insulin, interferons, irbesartan, irinotecan, isoconazole, isoprenaline, itraconazole, ivabradine, iodine and Jodderi derivatives, St. John's wort, potassium salts, ketoconazole, ketoprofen, ketotifen, lacidipine, lamotrigine, lansoprazole, laronidase, latanoprost, leflunomide, leminoprazole, lepirudin, lercanidipine, Leteprinim, letrozole, levacetylmethadol, levetiracetam, levocetirizine, levodopa, Levodrpropicin, levofloxacin, levomethadone, licofelone, Linezolid, Lipinavir, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine lodoxamide, lomefloxacin, lomustine, loperamide, lopinavir, loratadine, lornoxicam, losartan, lumefantrine, Lutropine, magnesium salts, macrolide antibiotics, Mangafodipir, maprotiline, mebendazole, mebeverine, meclizine, mefenamic, mefloquine, meloxicam, memantine, mepindolol, Meprobamat.Meropenem, mesalazine, mesuximide, metamizole, metformin, methadone, methotrexate, methyl (5-amino-4-oxopentanoate), methylnaloxone, Methylnaltrexone, methylphenidate, methylprednisolone, metixen, metoclopramide, metoprolol, metronidazole, mianserin, mibefradil, miconazole, mifepristone, miglitol, Miglustad, Milnacipra n, minocycline, minoxidil, misoprostol, mitomycin, mizolastine, modafinil, moexipril, montelukast, Moroctocog, morphinans, morphine and morphine derivatives, moxifloxacin, ergot alkaloids, nalbuphine, naloxone, naproxen, naratriptan, narcotine, natamycin, nateglinide, nebivolol, nefazodone, nelfinavir, neostigmine, Neramexan, nevirapine, nicergoline, nicethamide, nifedipine, niflumic acid, nimodipine, nimorazole, nimustine, nesiritide, nisoldipine, norfloxacin, Novaminsulfon, noscapine, nystatin, ofloxacin, Oktotride, olanzapine, olmesartan, olsalazine, oseltamivir, omapatrilat, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir, oxaceprol, oxacillin, oxaliplatin, oxaprozin, Oxcarbacepin, oxycodone, oxiconazole, oxymetazoline, palivizumab, palonosetron, pantoprazole, paracetamol, parecoxib, paroxetine, pegaspargase, peg interferon, Pegfilgrastrim, penciclovir, oral penicillins, pentazocine, Pentifyllin , pentoxifylline, peptide antibiotics, perindopril, perphenazine, pethidine, plant extracts, phenazone, Pheni Ramin, phenylbutyric acid, phenytoin, phenothiazines, phenserine, phenylbutazone, phenytoin, pimecrolimus, pimozide, pindolol, pioglitazone, piperazine, piracetam, pirenzepine, piribedil, pirlindol, piroxicam, Posaconazole, pramipexole, pramlintide, pravastatin, prazosin, procaine, promazine, propiverine, propranolol, Propionsaurederivate, Propyphenazon, prostaglandins, protionamide, proxyphylline, quetiapine, quinapril, Quinaprilat, quinupristin, ramipril, ranitidine, rabeprazole, raloxifene, ranolazine, rasburicase, reboxetine, Repaclinide, reproterol, reserpine, Revofloxacin, ribavirin, rifampicin, Riluzole, rimexolone, risedronate, risperidone, ritonavir, rituximab, Rivastimen, Risatriptan, rofecoxib, ropinirol, ropivacaine, rosiglitazone, rotigotine, roxatidine, roxithromycin, ruscogenin, rosuvastatin, rutoside and rutoside derivatives, sabadilla, salbutamol, salicylates, salmeterol, Saperconazole, thyroid hormones, scopolamine, selegiline, sertaconazole, sertindole, sertraline, sevelamer, sibutramine, sildenafil, Silicates, simvastatin, sirolimus, sitosterol, sotalol, Spagluminsäure, sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulphonamides, sulfasalazine, sulpiride, sultamicillin, sulthiame, sumatriptan, Suxamethoniumchlorid, tacrine, tacrolimus, tadalafil, TaMoIoI, talsaclidine, tamoxifen, tamsulosin, tasonermin, tazarotene, tegafur, tegaserod, telithromycin, telmisartan, temoporfin, temozolomide, Tenatoprazoi, tenecteplase, teniposide, tenofovir, tenoxicam, teriparatide, terazosin, terbinafine, terbutaline, terfenadine, teriparatide, terlipressin, tertatolol, testosterone and testosterone derivatives, tetracyclines, tetryzoline, tezosentan, theobromine, theophylline, theophylline, thiamazole, thiotepa, Thr. Growth factors, tiagabine, tiapride, tibolone, ticlopidine, tilidine, timolol, tinidazole, tioconazole, thioguanine, tiotropium, tioxolone, Tirazetam, tiropramide, Trofiban, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine, topiramate, topotecan, torasemide, tramadol, tramazoline, trandolapril, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, treprostinil, triamcinolone, and Triamcinolonderivate, triamterene, trifluperidol, trifluridine, trimetazidine, trimethoprim, trimipramine, trip land amine, triprolidine, trifosfamide, tromantadine, trometamol, Tropalpin, trovafloxacin, troxerutin, tulobuterol, trypsins, tyramine, tyrothricin, urapidil, ursodeoxycholic acid, theophylline ursodeoxycholic acid, valaciclovir, valdecoxib, valganciclovir, valproic acid, valsartan, vancomycin, vardenafil, Vecuroniumchlorid, venlafaxine, verapamil, verteporfin, vidarabine, vigabatrine, viloxazine, vinblastine, vincamine, vincristine, vindesine , vinorelbine, vinpocetine, Viquidil, vitamin D and The ivate of vitamin D, voriconazole, warfarin, xanthinol nicotinate, ximelagatran, xipamide, zafirlukast, zalcitabine, zaleplon, zanamivir, zidovudine, ziprasidone, zoledronic acid, zolmitriptan, Zolpidem, Zoplicon, zotepine and the like. Particularly preferred active ingredients

Preferred groups of active ingredients are analgesics, antibiotics, antidiabetics, antibodies, peptides, proteins, chemotherapeutics, corticoids / corticosteroids antiinflammatory agents, enzyme preparations hormones and their inhibitors, parathyroid hormones, digestive agents, laxatives, vitamins, cytostatic agents, active ingredients of other groups, which for kinetic reasons advantageous in deeper intestinal sections are applied.

Examples of particularly preferred active ingredients are mesalazine, sulfasalazine, Bethamethason-21 dihydrogenophosphat, hydrocortisone-21-acetate, cromolyn sodium, dexamethasone, olsalazine-Na, budesonide, prednisone Bismunitrat, karaya gum, methylprednisolone 21-succinate myrrh, coffee coal, Kamillenblüttenextrakt, preparations of Human placenta

Newer agents are to be taken from the literature or from relevant known to the person skilled in pharmaceutical databases: balsalazide, adalimumab, alemtuzumab, basiliximab, daclizumab, Ibritumomab, Ifliximab, cetuximab, palivizumab, rituximab, trastuzumab, other orally administered peptides (eg RDP 58) interleukin 6, interleukin 12, llodecakin (interleukin 10), nicotine tartrate, 5-ASA conjugates (CPR 2015), monoclonal antibodies against interleukin 12, Diethyldihydroxyhomospermin (DEHOHO) diethylhomospermine (DEHOP), cholecystokinin (CCK) antagonist (CR 1795), 15 amino acid fragment of a 40 kD peptide from stomach juice (BPC 15) Glucocorticoidanalogon (CBP 1011), natalizumab, infliximab (REMICADE) N-de-acetylated Lysoglycosphingolipid (WILD 20) Azelastine, tranilast, Sudismase, phosphorothioate Antisensoligonucleotid (ISIS 2302), Tazofelone Ropivacaine, 5 lipoxygenase inhibitor (A 69412), sucralfate The active ingredients can if desired also in the form of their pharmaceutically annehmb arene salts or derivatives can be used, and in the case of chiral active compounds both optically active isomers and racemates or diastereoisomer mixtures can be employed. The active compounds can also as physikatische or chemical conjugates are present (Polymer Conjugates drug designation, z. B. peptide / protein-drug complexes). If desired, the novel compositions can also contain two or more active pharmaceutical ingredients.

EXAMPLES

Test description equipment

Fluidized bed apparatus Hüttlin Mycrolab

Nozzle: three-component nozzle, nozzle diameter: 0.8 mm

Procedure: Bottom spray

Hose pump: Ismatec MCP

Coatings (Coaiing) Material

Theophylline pellets (particle diameter: 0,8 - 1. 2 mm) Active ingredient content: about 93% batch size: 200 and 800g

coating conditions

Inlet temperature: 33 - 43 0 C process temperature: 25 - 31 0 C Spraying pressure: from 0.6 to 0.75 bar microclimate: 0,4 - 0,5 bar

Spray rate: at 200g batch size: ca. 12 g / min / kg at 800g batch size: approximately 5 g / min / kg

Sampling at 6 and 10% polymer application. polymers

Type of polymer (I)

Eudragit® FS 30 D (FS30 D):

Methyl acrylate methyl methacrylate methacrylic acid copolymer

Polvmertypen (II)

Eudragit® NE 30 D (NE30 D): methyl methacrylate ethyl acrylate copolymer

KOLLICOAT® SR 30 D: polyvinyl acetate

Aquacoat® ECD: ethyl cellulose polymer

(All 30% aqueous dispersions) Plasticizer: DBS dibutyl sebacate

mixtures

Figure imgf000049_0001
formulation

Examples

Spray suspension for 800g pellets and 15% polymer application:

Suspension [g] solid [g] share [%]

Polymer blend 400 120 93.4

Gycerinmonostearat 6 6 4.7

Polysorbate 80 7.3 2.4 1, 9

Demineralised water 228.7 _ -

642.0 128.4 100

DM content spray suspension: 20.0%

Preparation of the spray suspension:

Deionised water and polysorbate 80 are heated with gentle stirring to 75 ° C. For this, the glycerol is added and homogenized with vigorous stirring for about 30 minutes. After cooling to room temperature, the addition of the polymer dispersions and the plasticizer takes place. Where required a coagulum on mixing the dispersions is avoided by previous matching of the pH values. Drug release (tables)

USP release test

The Freisetzu ngstest carried out according to USP 28-NF23, General Chapter <711>, Dissolution, Apparatus 2 (paddle), Method <724> "Delayed Release (Enteric Coated) Articles-General General Drug Release Standard", Method B (100 rpm, 37 0 C) with the following modification: The coated pellets were first placed for 120 minutes in artificial gastric juice (USP) at pH 1, 2 tested for gastric juice resistance, then was re-buffered with phosphate buffer at pH 7.5, which corresponds to an artificial intestinal environment, the active compound concentration. in the test medium was determined by photometry.

After 120 minutes to be released no more than about 5% of the active ingredient. After 180 min, corresponding to 60 minutes at pH 7.5, a drug release rate of 5 to 95%, preferably sought by 10 to 50%.

The results are summarized in Tables 1 to third The indication 6, 10 and 15% are respectively the dry weight of the coating relative to the core weight of.

Table 1

Figure imgf000052_0001

table 2

Figure imgf000053_0001

table 3

Figure imgf000054_0001

Claims

1. Use of a mixture of 2 to 60 wt .-% of one or more polymers (I) with 40 to 98 wt .-% of one or more polymers (II), wherein
the polymer (I) is a (meth) acrylate copolymer containing 90% to 100 wt .- free-radically polymerized units of 40 to 95 wt .-% of Cr to C 4 -alkyl esters of acrylic or methacrylic acid and 5 to 60 wt .-% units of (meth) acrylate monomers having an anionic group, and 0 to 10 wt .-% of other vinylically polymerizable monomers, and
the polymer (II) is the polymer (I) miscellaneous vinyl polymer or a polysaccharide or a derivative of a polysaccharide containing 88 to 100% neutral monomer units and up to 12 wt .-% of polymerized monomer units having ionic groups,
for preparing a coated dosage form comprising an active substance-containing core and a polymeric coating from the mixture of polymers (I) and (II),
characterized, in that
the glass transition temperature of the polymer (I) not more than 70 0 C, and a drug release profile is obtained, wherein the active ingredient compared with one with the polymer (I) alone coated pharmaceutical form, starting at the same pH value, however, slowed down is released.
2. Use according to claim 1, characterized in that the polymer (I) is a copolymer of 10 to 30 wt .-%, methyl methacrylate 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% methacrylic acid.
3. Use according to claim 1, characterized in that the polymer (I) is a copolymer derived from up
20-34 wt .-% methacrylic acid and / or acrylic acid,
20 till 69 wt .-% of methyl acrylate and 0 to 40 wt .-% ethyl acrylate and / or optionally 0 to 10 wt .-% further vinylically copolymerizable monomers
composed, with the proviso that the glass transition temperature of the copolymer is at most 60 0 C.
4. Use according to claim 1, characterized in that the polymer (I) is a copolymer derived from up
20-33 wt .-% methacrylic acid and / or acrylic acid,
5 to 30 wt .-% of methyl acrylate and 20 to 40 wt .-% ethyl acrylate and more than 10% to 30 wt .- butyl methacrylate and optionally
0 to 10 wt .-% of further vinylically copolymerizable monomers, where the proportions of the monomers add up to 100 wt .-%,
composed, with the proviso that the glass transition temperature of the copolymer is 55 to 70 0 C.
5. Use according to claim 1, characterized in that the polymer (II) is a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethylammoniumethyl methacrylate, a polyvinyl-pyrrolidones (PVP), polyvinyl alcohols, polyvinyl alcohol -Polyethylenglycol graft copolymer, starch and derivatives thereof, polyvinyl acetate (PVAc), vinyl acetate-vinylpyrrolidone copolymer, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), Hydroxymehylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose ( is MC)), Celluloseester, cellulose glycolate or a mixture of said polymers.
6. Use according to claim 5, characterized in that the polymer (II) is a copolymer of 20% to 40 wt .- ethyl acrylate and 60 to 80 wt .-% methyl methacrylate.
7. Use according to claim 5, characterized in that the polymer (II) a copolymer of 50-70 wt .-% methyl methacrylate, 20 - 40 wt .-% ethyl acrylate and 12 to 2 weight trimethylammoniumethyl methacrylate chloride.
8. Use according to one or more of claims 1 to 7, characterized in that the polymer coating comprises 2 to 20 wt .-% with respect to the weight of the active ingredient-containing core by weight.
9. Use according to one or more of claims 1 to 8, characterized in that the active substance starts at the pH at which the polymer (I) to dissolve, in the USP release test is released in 60 minutes to less than 50% ,
10. Use according to one or more of claims 1 to 9, characterized in that the coated dosage form in pellet form contained in a multiparticulate pharmaceutical form, in particular in pellet-containing tablets, minitablets, capsules, sachets or reconstitutable powders.
11.Arzneiform containing, characterized in a drug-containing core which is coated with a polymer mixture coating the mixed coating a mixture of 2 to 60 wt .-% of one or more polymers (I) with 40 to 98 wt .-% of one or is more polymers (II),
characterized, in that
the polymer (I) is a copolymer of 10 to 30 wt .-%, methyl methacrylate 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt% methacrylic acid and is
the polymer (II) is the polymer (I) miscellaneous vinyl polymer or a polysaccharide or a derivative of a polysaccharide which is composed about 88 to 100% of neutral monomer units and up to 12 wt .-% monomer units may contain with ionic residues.
12. The dosage form of claim 11, characterized in that the polymer (II) is a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethylammoniumethyl methacrylate, a polyvinyl-pyrrolidones (PVP), polyvinyl alcohols, polyvinyl alcohol -Polyethylenglycol graft copolymer, starch and derivatives thereof, polyvinyl acetate (PVAc), vinyl acetate-vinylpyrrolidone copolymer, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), Hydroxymehylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose ( is MC)), Celluloseester, cellulose glycolate or a mixture of said polymers.
13. The dosage form of claim 12, characterized in that the polymer (II) is a copolymer of 20% to 40 wt .- ethyl acrylate and 60 to 80 wt .-% methyl methacrylate.
14. The dosage form of claim 12, characterized in that the polymer (II) a copolymer of 50-70 wt .-% methyl methacrylate, 20 - 40 wt .-% ethyl acrylate and 12 to 2 weight trimethylammoniumethyl methacrylate chloride.
15. Pharmaceutical form according to one or more of claims 11 to 14, characterized in that the polymer coating 2 to 20 wt .-% with respect constitutes the weight of the active ingredient-containing core.
16. Pharmaceutical form according to one or more of claims 11 to 15, characterized in that the active ingredient is released at the pH value at which the polymer (I) begins to dissolve, in the USP release test in 60 minutes to less than 50% ,
17. Pharmaceutical form according to one or more of claims 11 to 16, characterized in that it is in the form of a multiparticulate pharmaceutical form, in particular as a pellet-containing tablet, mini tablet, capsule, sachet or dry juice.
PCT/EP2006/001949 2005-05-25 2006-03-03 Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating WO2006125483A1 (en)

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US11909315 US20080193522A1 (en) 2005-05-25 2006-03-03 Use of Polymer Mixtures For the Production of Coated Pharmaceutical Formulations and Pharmaceutical Formulation With Mixed Polymeric Coating
EP20060723193 EP1890682B1 (en) 2005-05-25 2006-03-03 Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating
ES06723193T ES2628962T3 (en) 2005-05-25 2006-03-03 Use of polymer mixtures for the production of coated pharmaceutical forms and dosage form with mixed polymer coating
JP2008512703A JP5582701B2 (en) 2005-05-25 2006-03-03 Use of a polymer mixture for the preparation of coated pharmaceutical formulations and polymer mixture coated pharmaceutical preparations
CA 2606587 CA2606587C (en) 2005-05-25 2006-03-03 The use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating
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